Age-related macular degeneration (AMD) is a major cause of blindness that is characterized by pathologic changes at the retinal pigment epithelium-choriocapillaris interface. We recently found that vascular loss of the choriocapillaris is relatedto the earliest clinical signs of AMD, and that a reduced vascular density and increased number of ghost vessels are related to the size and number of drusen and other subRPE deposits. Activation of the terminal complement pathway and formation of the membrane attack complex (MAC) at the level of the choriocapillaris is a likely cause of vascular loss in AMD. In this proposal we seek to identify the molecular and cellular responses of choroidal endothelial cells injured by MAC; to identify small molecules that protect choroidal endothelial cells against MAC-mediated lysis; and to develop and test avenues for the eventual replacement of lost endothelial cells. We anticipate that completion of these aims will result in important new understanding of mechanisms of protecting the choroid in early AMD, which may lead to new therapies for this blinding disease.